JAC Advance Access originally published online on November 12, 2003
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Journal of Antimicrobial Chemotherapy (2003) 52, 967-973
© 2003 The British Society for Antimicrobial Chemotherapy
Phage lytic enzymes as therapy for antibiotic-resistant Streptococcus pneumoniae infection in a murine sepsis model
1 Centro Nacional de Microbiología, Instituto de Salud Carlos III, 28220 Majadahonda, Madrid; 2 Departamento de Microbiología Molecular, Centro de Investigaciones Biológicas, CSIC, Ramiro de Maeztu 9, 28040 Madrid, Spain
Received 16 July 2003; returned 15 September 2003; revised 18 September 2003; accepted 25 September 2003
Objectives: Phage-coded lysins, i.e. murein hydrolases, are enzymes that destroy the cell wall of bacteria. A rapid killing of Streptococcus pneumoniae in the nasopharynx of mice has been described recently using a phage-coded murein hydrolase (enzybiotic). The in vivo effects of a dose-ranging treatment, using either of the phage-coded lytic enzymes Cpl-1 lysozyme or the Pal amidase, have been investigated here in a murine sepsis model.
Methods: Purified Pal amidase and/or Cpl-1 lysozyme were used alone or in combination. These enzymes were injected intraperitoneally at different times after challenge with 5 x 107 cfu of a type 6B, antibiotic-resistant S. pneumoniae clinical isolate.
Results: Animals challenged with 5 x 107 cfu of this strain alone died within 72 h, whereas a single intraperitoneal injection of Cpl-1 or Pal (200 µg; 1100 U) administered 1 h after the bacterial challenge was sufficient to effectively protect the mice, according to unpaired t-test (P < 0.0001). Bacteraemia in unprotected mice reached colony counts >107 cfu/mL, whereas the mean colony count in lysin-protected animals was <106 cfu/mL over time and ultimately became undetectable. Interestingly, a synergic effect in vivo was observed with the combined use of 2.5 µg each of Cpl-1 and Pal.
Conclusions: Our findings suggest strongly that phage lysins protect animals from bacteraemia and death. Moreover, the simultaneous attack of the pneumococcal peptidoglycan by a lysozyme and an amidase leads to a remarkable effect through enhanced destruction of the bacterial cell wall. The benefits of therapy with enzybiotics against pneumococcus reported here might warrant the examination of alternative strategies for the treatment of diseases caused by clinically relevant pathogens.
Keywords: enzybiotics, pneumococcus, phage, lytic enzymes
* Corresponding author. Tel: +34-91-8373112; Fax: +34-91-5360432; E-mail: ruben{at}cib.csic.es
Members of the Spanish Pneumococcal Infection Study Network are listed in the Acknowledgements.
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